Unstable acetonalkamins and process of making same.



UNITED STATES PATENT mace.

CARL HARRIES, OE BERLIN, GERMANY, ASSIGNOR TO THE OHEMISOHE FABRIK AUF ACTIEN, VORMALS E. SGHERING, OF SAME PLACE.

UNSTABLE ACETONALKAMINS AND PROCESSOF MAKING SAME.

SPECIFICATION forming part of Letters Patent No. 663,754, dated December 1 1, 1900.

Application filed December 11,1897. serial No. 661,514. (No specimens.) V

T0 aZZ whom it may concern Be it known that LCAEL HARRIE's,of Berlin, in the Empire of Germany, have invented certain new and useful Improvements in the Man ufacture of Unstable Unsymmetrical Acetonalkamins and Acidyl Derivatives therefrom, (for which Letters Patent have been obtained in Germany, No. 95,620, dated May 10, 1896, and in Great Britain, No. 20,697 of 1896,) of which the following is a specification.

The present invention relates to the production of acidyl derivatives of the unstable modifications of the unsymmetrical acetonal kamins, in which for the present invention also their n-alkali derivativest'. 6., normal alkyl derivatives-are included.

I have discovered that by reducing the unsymmetrical bases of the triacetonamin series-as, for example, vinyldiacetonamin, valeryldiacetonamin, oenanthdiacetonamin, benzylidenediacetonamin, piperonylenediacetonamin- NH Vinyldiacetonamin.

Oenantlldiacetonamin.

Piperonylenediacetonamin.

as Well as generally the analogously-constituted unsymmetrical aceton amin bases,which contain other aliphatic or aromatic radicals joined to the alpha-asymmetrical carbon, a 7 mixture of two isomeric alkamins is produced, one of which represents the stable the other the unstable modification. The constitution of the stable and unstable alkamins corresponds to the general chemical formula:

OH-IOH CH 3 2 I NH modifications are produced, while the stable forms are not obtained. Of course the unstable forms may also be obtained in the manner described in my application, which is entitled Improvement-s in the manufacture of isomeric unsymmetrical acetonalkamins, 850., Serial No. 661,513, filed December 11, 1897. The electrolytic reduction is best effected in weak alkaline solution. The electrolytic hydrogen reacts upon the greatest part of the aoetonamins only in alkaline solutionfor example, upon vinyldiacetonamin, valeryldiacetonamin. In these cases no reduction takes place in acid solution. The use of a diaphragm is preferred. The '11 um ber of volts and amperes may be varied within a wide range. used in my experiments. The hydrogen pole had a surface of about four square inches and inches.

A. PRODUCTION OF THE UNSTlABLE UNSYM- I which for the purposes of the present inven- METRICAL AGETONALKAMINS.

1. Production of the unstable vtnyldz'ctcetonaZlcamin.-The cathodic cell of an electrolytic apparatus is filled with a solution of one kilogram of vinyldiacetonamin in a ten-percent. solution of sulfate of ammonia,while the anodic cell is filled with ten-per-cent. sulfuric acid. Then the electrolytic reduction is commenced. Now and then a small quantity of sulfate'of ammonia or of sulfuric acid is added to the cathodic cell. Carem ust be taken that the reaction always remains alkaline. As soon as the reduction is finished an excess of soda-lye is added, whereby the alkamin base is precipitated. After sucking the liquid off the base is dissolved in boiling alcohol. On cooling the unstable vin'yldiacetonalkamin crystallizes therefrom in glossy needles melting at 161 or 162 centigrade. The motherlye is evaporated with hydrochloric acid to dryness. On treating the residue with cold absolute alcohol all is dissolved excepting a culty. As soon as the reduction is finished the.

product of the reaction is overs-aturated with soda-lyeand shaken withet-her. After distilling the ether an oil remains behind which grad ually passes into a solid state. On adding cold petroleumether the unstable valeryldia- *cetonalkamin formed is separated as a white powder. It crystallizes from a mixture of Six a'mperes and four volts were petroleum ether and benzene into glossy prisms melting at 93 or 9.4" centigrade.

The unstable forms of oenanthdiacetonalkamin, benzylidenediacetonalkamin, piperonylenediacetonalkamin are produced in a similar way to that described for vinyldiacetonalkamin and valeryl'diacetonalkamin.

The unstable oenanthdiacetonalkamin crystallizes out of ligroin in glossy scales melting at 77 to 79 centigrade.

The unstable benzylidenediacetoualkamin crystallizes out of ligroin and has a meltingpoint of about 68 centigrade.

The unstable piperonylenediacetonalkamin crystallizes from benzene in needles melting at 108 to 109 contigrade.

B. PRODUCTION OF AOIDYL DERIVATIVES FROM THE UNSTABLE UNSYMMETRIOAL ACETONALKAMINS.

If the hydrogen atomof the hydroxyl inthe I unstable unsymmetrical acetonalkamins (in tion their n-alkyl derivatives--that is, normalalkyl deri v ativesare also included) be replaced by acid radicals, preferably with the ph'enylglycolyl or mande'lic acid group O H OH. OH OO tropic-acid gro'up OH OH valuable alkaloids are obtained. The composition of theso-formed acidyl compounds answers the chemical formula in which formula H signifies a hydrogen atom which can be replaced by an acidyl group, R an aliphatic or'aromatic radical, and H* a hydrogen atom which can be replaced by an alkyl group.

The bases expressed by the before-mentioned formula areinsoluble in water and decompose upon boiling with watery or alcoholic alkali into the respective unstable alkamin base (non-alkylated or-alkylated) and into a salt of that acid the radical of which has been sustituted for thehyd rogen atom of the hydroxyl. The bases combine with inorganic and organic acids, thus forming the corresponding salts which possess especially mydriatic properties.

In the following description the letter n before methyl or methylated indicates that in these compounds the hydrogen atom of the N. H. group can be replaced by the methyl group.

Emamples.

1. PhenylgtycoZyZ-n-methyZ-vinyldiacetonal hamtn from the unstable vtnytdtacetonalhw min melting at 161 or 162.The n-methylvinyldiacetonalkamin necessary for the purpose is preferably produced in the following manner: Molecular quantities of vinyldiacetonalkamin and methyl iodid, dissolved in forty-per-cent. methyl alcohol, are allowed to stand at the temperature of the atmosphere for about forty-eight hours. After that time a mixture of the iodic-acid salt of n-methylvinyldiacetonalkamin, unaltered vinyldiacetonalkamin, and n-methyl-vinyldiaoetonalkamin iodmethylate separate out. The mixture is evaporated to dryness, taken up with water,su persatu rated with potash,and shaken out several times with ether, whereby the ammonium compound remains behind undissolved. After evaporation of the ethereal solution it is boiled several times with petroleum ether. The unaltered vinyldiacetonalkamin is thereby retained. The n-methylvinyldiacetonalkamin crystallizes out of petroleum ether on cooling in silk glossy needles meltingat 84 or 85 centigrade. The methyl derivative from the vinyldiacetonalkamin, as well as from the other unsymmetrical acetonalkamins, may also be obtained by heating the alkamin with an excess of watery solution of formaldehyde on a water-bath for about ten hours. From the carbonate of alkamin thus formed the n-methylated alkamin base is set in freedom by sodalye. This method of methylation yields the best results.

To produce the phenylglycolyl derivative, Ladenburgs method is the best to follow. A thin solution of the n-methylated base to which an excess of mandelic acid is added is several times evaporated with smallquantities of hydrochloric acid. The residuum is taken up with water, mixed withafew drops of hydrochloric acid, and shaken several times with ether. The acid solution is then supersaturated in the cold with soda solution and shaken out with ether, whereupon the ether residuum is washed with water. The oil remaining behind after the evaporation of the ether gradually solidifies to a crystalline mass, which is washed with cold petroleum ether, in which the alkaloid is difficnltly soluble. It crystallizes out of hot petroleum ether in small pieces composed of very fine needles, melting at 112 or 113 centigrade. The hydrochloric-acid salt is extraordinarily deliquescent, and it possesses a strong mydriatic action in a two-per-cent. solution. The

mandelic-acid derivative may also, but little advantageously, be obtained by treating the vinyldiacetonalkamin melting at 161 or162 with mandelic acid according to Ladenburgs method, and methylating the phenylglycolylvinyldiacetonalkamin produced thereby in small quantities with methyl iodid. The phenylglycolyl derivatives may also be produced by the action of mandelic anhydrid in place of mandelic acid, or by passing hydrochloric acid through a melted mixture of the alkamin and mandelic acidfor example, at about centigrade. In the same way the unstable vin yldiacetonalkamin contained in- The product of reaction obtained by Ladenburgs method is mixed with soda solution,

repeatedly shaken with ether, the ethereal solution dried with potash, evaporated, and the product treated with cold water. The greater portion of the unstable vinyldiacetonalkamin not reacted upon is thereby dissolved, while the phenylglycolyl alkaloid remains behind undissolved. It has a meltingpoint of 150 to 177 centigrade. It has hitherlo not been obtained in a pure state. 'It contains, however, mandelic acid in a great measure combined,which after saponification of the alkaloid is easily demonstrated. The salts of the base possess weak but recognizable mydriatic action.

4. Tropyl n methyl otnytdtacetonatkamtn.Proceed exactly as before by repeatedly evaporating upon the water-bath-the solution in water of the n-methylated vinyldiacetonalkamin mixed with tropic acid, hydrochloric acid beingadded from time to time. The further working is carried out as under Example 1. After washing the crude product with water tropyln methyl vinyldiacetonalkamin remains behind as a quickly-solidifying oil. The base is very difficultly soluble in water. It is easily saponitied by a boiling soda solution. The hydrochloric acid salt is very deliquescent. It possesses strong mydriatic action very similar to the hydrochloricacid salt of the corresponding mandelic-acid derivative.

5. Beneoyl derivative from the unstable vz'ng ldiacetonalltamtn.The ethereal solution of the base melting at 161 or 162 centiacetonalkamin.

grade is first transformed into the hydrohydrochloric-acid salt is obtained in a microcrystalline statebymixing an ethereal solution of the base with ethereal hydrochloric acid. It possesses mydriatic and anesthetic properties.

6. Benzoyl n methyl oinyld'iacetonalkamt'n.-The benzoyl-n-met-hyl product is ob tained either by the action of methyl iodid upon the unmethyl-ated-base obtained, as under Example 5, by heating molecular quantities in methylalcoholic solution with methyl iodid or by benzoy-latin-g -n-methyl-vinyldi- The resulting base is an oil. The hydrochloric-acid salt possesses mydriatic and anesthetic properties.

'7. Phen'ylacetyl vinyldz'acetonalkamt'n. Phenylacetyl vinyldiacetonalkamin is ob- I tained by the reaction of pheuylaceticacid chlorid upon the unstable alkami-n and also forms an oil. It splits up by boiling with caustic-soda solution into phenylacetic acid and vinyldiacetonalka-min melting at 161 or 162 centigrade. The salts are very easily soluble in water and possess Weak mydriatic and strong anesthetic properties. In the same way as the unstable vinyldiaceto-nalkamin the unstable modificationsof analogouslyconstituted unsym metrical acetona'l kaminssuch as, for example, the valeryl, piper-onylene, benzylidene, and oenanthdiacetonalkamins-may be transformed into acidyl derivatives.

8. Phenylglycolyl vaZeryZd-iacetonalkamin.lt has a melting-pointof 141 to 143 centigrade. Its mydriatic action is minimal.

' 9. PhenylglycolyZ-n-methyZ-valeryldiacetonaZ-7camin.-The base is an oil, as is the product of the first step-namely, the n-methyl- Valery]diacetonalkamin, which is produced in an analogous manner to the n-methylvinyldiacetonalkami-n. The alkaloid base is itself insoluble in water, but easily soluble'in alcohol, ether, and warm petroleum ether. It possesses pronounced mydriatic action. By boiling the base with caustic-soda solution it is split up into mandelic acid andnmethyl-valeryldiacetonalkamin. The mandelic acid maybe easily recognized by acidifying and shaking with ether. The salts are all easily soluble in water.

10. PhenylglycoZyZ-n-methyZ-benzyZidenedtacetonalkamin.'lhe n-methyl derivative of the unstable benzylidenediacetonalkamin melts at 84 to 88 centigrade and crystallizes out of a mixture of benzene and petroleum seam ether. The mandelic derivative of this base is an oil which has only Weakmydriatic properties. The saltsareeas-ily soluble in water.

11. Phenylglycolyl-n methyl-oena'nthd'iacetonaZkamt'n.The n-methyl derivative of the unstable oenauthdiacetonalk-amin is .an oil,

as is also the mandelic derivative obtained therefrom, which possesses recognizable mydriatic action.

12. PhenylglycolyZ-n-methyl-pipronyl'nedtacetonalkamt'n The n-methyl: piperonylenediacetonalkami-n of the unstable piperonylenediacetonalkamtn crystallizes out of benzene in-satin shining leaves having a melting-point of 152 or 153 cent-igrade. The man delic derivative remains after distilling off the ether as a crystalline powder melting at about 150 centigrade. It possesses mydri= atic properties. I

By the term acetena-lkamins in the following claims I intend to includealso the derivatives of acetonalkzamins.

I wish it to be understood that I do not claim under this application the acidyl compounds of the stable vinyldizacetonalkamin melting at 138 centigrade and of its .alkyl derivatives as new products or the method of production :of isuchacid-yl 'derivati ves'f ro m the stable vinyldiaoetonalkamin melting at 138 centigrade, which form thesubject of an application for patentfiled by George Merling and Albrecht Schmidt, Serial No. 607,110,

filed September .26, 1896.

I. claimyas my invention- 1. The herein-described,process of'obtaining acidyl compounds of the unstable modifications of thennsymmetrical cyclical. acetonalk ami-ns consisting insubjecting these alkamins to the action-of-anacidyl reagent and thus substituting the corresponding acidyl group for the hydrogen atom of the hydroxyl group of thesaid alkamin.

2. The herein-described process of obtaining ,ac-idyl compounds of the unstable unsymmetrical acetonalkamins consisting in first subjecting the corresponding amiu bases to the action of the electric current to produce the unstable alkamins and then subjecting these alkamins to'the action of an acidyl reagent, as andfor the purposeset forth.

3. As inewchemical products the hereindescribed unstable.acetonalkamins, thecomposition of which products answers the general formula:

H -O-CH I R/M T H cHnc k) c R Nle in which H signifies a hydrogen atom which can be replaced by an acidyl group, R an aliphatic or aromatic radical and H a hydrogen atom which-can be replaced by an alkyl 10 which was substituted for the hydrogenatom of the hydroXyl-oombined with inorganic and organic acids form thecorresponding salts which have especially nlydriatic properties. In testimony whereof I have hereunto set my hand this 26th day of November, 1897.

CARL HARRIES.

Witnesses WOLDEMAR HAUPT, HENRY HASPER. 

